chr2-178586693-G-A

Variant names:

• chr2-178586693-G-A
• rs2042996
• NM_001267550.2:c.64208C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.64208C>T​(p.Thr21403Ile) variant causes a missense change. The variant allele was found at a frequency of 0.275 in 1,612,818 control chromosomes in the GnomAD database, including 73,844 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11527 hom., cov: 32)
  • Exomes 𝑓: 0.27 (62317 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 5.88
• Publications: 41 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.70831E-6).
• BP6: Variant 2-178586693-G-A is Benign according to our data. Variant chr2-178586693-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.64208C>T	p.Thr21403Ile	missense	Exon 308 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.59285C>T	p.Thr19762Ile	missense	Exon 258 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.56504C>T	p.Thr18835Ile	missense	Exon 257 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.64208C>T	p.Thr21403Ile	missense	Exon 308 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.64052C>T	p.Thr21351Ile	missense	Exon 306 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.63932C>T	p.Thr21311Ile	missense	Exon 306 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54190 AN: 151798 Hom.: 11474 Cov.: 32

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.706

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.326

GnomAD2 exomes AF: 0.351 AC: 87295 AN: 248600 AF XY: 0.348

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.285

Gnomad EAS exome AF: 0.709

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.267 AC: 389609 AN: 1460900 Hom.: 62317 Cov.: 35 AF XY: 0.272 AC XY: 197731 AN XY: 726748

African (AFR) AF: 0.540 AC: 18042 AN: 33420

American (AMR) AF: 0.425 AC: 18985 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 7451 AN: 26110

East Asian (EAS) AF: 0.696 AC: 27573 AN: 39610

South Asian (SAS) AF: 0.507 AC: 43752 AN: 86224

European-Finnish (FIN) AF: 0.276 AC: 14756 AN: 53396

Middle Eastern (MID) AF: 0.307 AC: 1766 AN: 5756

European-Non Finnish (NFE) AF: 0.215 AC: 239112 AN: 1111366

Other (OTH) AF: 0.301 AC: 18172 AN: 60330

GnomAD4 genome AF: 0.357 AC: 54309 AN: 151918 Hom.: 11527 Cov.: 32 AF XY: 0.367 AC XY: 27270 AN XY: 74238

African (AFR) AF: 0.529 AC: 21922 AN: 41454

American (AMR) AF: 0.380 AC: 5797 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 997 AN: 3466

East Asian (EAS) AF: 0.706 AC: 3614 AN: 5116

South Asian (SAS) AF: 0.519 AC: 2493 AN: 4806

European-Finnish (FIN) AF: 0.286 AC: 3025 AN: 10578

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15161 AN: 67928

Other (OTH) AF: 0.334 AC: 705 AN: 2108

Alfa AF: 0.280 Hom.: 21611

Bravo AF: 0.371

TwinsUK AF: 0.211 AC: 784

ALSPAC AF: 0.214 AC: 824

ESP6500AA AF: 0.508 AC: 2009

ESP6500EA AF: 0.220 AC: 1837

ExAC AF: 0.351 AC: 42389

Asia WGS AF: 0.617 AC: 2143 AN: 3478

EpiCase AF: 0.219

EpiControl AF: 0.228

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.027
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Benign	0.77
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0000037	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-3.6	N
PhyloP100		5.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	3.0	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.058
MPC		0.090
ClinPred		0.013	T
GERP RS		6.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2042996; hg19: chr2-179451420; COSMIC: COSV60092466; COSMIC: COSV60092466;